1. Field of the Invention
This invention is directed to novel local anesthetic compounds, pharmaceutical composition containing these compounds, methods of use and methods for preparing these compounds.
2. State of the Art
Local anesthetics are believed to prevent or relieve pain by interrupting nerve conduction. More specifically, such compounds are believed to a specific receptor site within the pore of the sodium channels in the nerves and block ion movement through this pore. Currently, a number of local anesthetics such as benzocaine, bupivacaine, cocaine, lidocaine, mepivacaine are available and are being used as to prevent or relieve pain. However, these drugs have limited utility as they cause adverse side effects such as cardiotoxicity and CNS side effects and/or have short duration of action. Accordingly, there is a need for local anesthetics that have longer duration of action while reducing the undesired side effects.
The compounds of the present invention fulfill this need.
This invention provides novel compounds that are useful as inhibitors of Na+ channels and are effective as local anesthetics.
Accordingly, in one aspect, this invention is directed to a compound of Formula (I):
L1-X-L2xe2x80x83xe2x80x83(I)
wherein:
L1 is represented by:
(i) a group of formula (a): 
xe2x80x83where:
E is aryl, heteroaryl, heterocycle, or cycloalkyl;
G is xe2x80x94NR7xe2x80x94 (where R7 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle), xe2x80x94Oxe2x80x94 or xe2x80x94S(O)nxe2x80x94 (where n is 0, 1 or 2);
R1 and R2 are independently selected from the group consisting of hydrogen, alkyl, halo, cyano, hydroxy, alkoxy, amino, xe2x80x94NRcRd (where Rc is hydrogen or alkyl and Rd is alkyl), carboxy, and carboxyalkyl; or R1 and R2 when adjacent to each other together form xe2x80x94OCH2Oxe2x80x94 or xe2x80x94O(CH2)2Oxe2x80x94;
R3 and R4 are independently selected from the group consisting of hydrogen, alkyl, halo, cyano, hydroxy, alkoxy, amino, xe2x80x94NRcRd (where Rc is hydrogen or alkyl and Rd is alkyl), carboxy, and alkoxycarbonyl; or R3 and R4 together with the carbon atom to which they are attached form a carbonyl group;
R5 and R6 are independently selected from the group consisting of hydrogen and alkyl; or
(ii) a group of formula (b): 
xe2x80x83wherein:
J is xe2x80x94Oxe2x80x94, or xe2x80x94S(O)nxe2x80x94 (where n is 0, 1, or 2); and
E, G, R1, R2, R3, R4, R5 and R6 are as defined above;
X is a linker;
L2 is represented by:
(iii) a group of formula (c): 
xe2x80x83wherein:
Ar is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl and substituted cycloalkyl;
W is selected from a covalent bond, xe2x80x94[CR8R9]rxe2x80x94, xe2x80x94[CR8R9]rxe2x80x94C(O)xe2x80x94, xe2x80x94OC(O)xe2x80x94[CR8R9]rxe2x80x94, xe2x80x94C(O)O[CR8R9]rxe2x80x94, xe2x80x94Oxe2x80x94[CR8R9]rC(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NHxe2x80x94[CR8R9]rxe2x80x94, or xe2x80x94NHxe2x80x94C(O)[CR8R9]r where r is an integer of 0 to 10, and R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl and xe2x80x94NRaRbxe2x80x94 where Ra and Rb are both alkyl; or
(iv) a group of formula (d): 
xe2x80x83where:
U is aryl, heteroaryl, heterocycle, or cycloalkyl;
Wa is xe2x80x94NR16xe2x80x94 (where R16 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle), xe2x80x94Oxe2x80x94 or xe2x80x94S(O)nxe2x80x94 (where n is 0, 1 or 2);
R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, halo, cyano, hydroxy, alkoxy, amino, monosubstituted or disubstituted amino, carboxy, and carboxyalkyl; or R10 and R11 when adjacent to each other together form xe2x80x94OCH2Oxe2x80x94 or xe2x80x94O(CH2)2Oxe2x80x94;
R12 and R13 are independently selected from the group consisting of hydrogen, alkyl, halo, cyano, hydroxy, alkoxy, amino, monosubstituted or disubstituted amino, carboxy, and alkoxycarbonyl; or R12 and R13 together with the carbon atom to which they are attached form a carbonyl group;
R14 and R15 are independently selected from the group consisting of hydrogen and alkyl; or
(v) a group of formula (e): 
xe2x80x83where:
V is xe2x80x94Oxe2x80x94, or xe2x80x94S(O)n1xe2x80x94 (where n1 is 0, 1, or 2); and
U, Wa, R10, R11, R12, R13, R14 and R15 are as defined above; and individual isomers, mixtures of isomers, prodrugs, and pharmaceutical acceptable salts thereof provided that:
when L1 is a group of formula (a) wherein E is phenyl, R1 is methyl and is at the 8-position of the quinazolone ring, R2, R5, R6 are hydrogen, G is xe2x80x94NR7xe2x80x94 where R7 is morpholin-1-ylcarbonylmethyl; X is 1,4,10,13-tetraoxa-7,16-diazacyclooctadec-7,16-diyl; L2 is Arxe2x80x94Wxe2x80x94 where W is methylene, then Ar is not phenyl and is named as 7-[8-methyl-3-(morpholin-4-ylmethyl]-4-(3H)-quinazolinon-2-yl)methyl-16-[(R)-(2-benzyl)]-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane; and
when L1 is a group of formula (a) wherein E is phenyl, R1 is methyl and is at the 8-position of the quinazolone ring, R2, R5, R6 are hydrogen, G is xe2x80x94NR7xe2x80x94 where R7 is tetrahydropyran-4-ylaminocarbonylmethyl; X is 1,4,10,13-tetraoxa-7,16-diazacyclooctadec-7,16-diyl; L2 is Arxe2x80x94Wxe2x80x94 where W is xe2x80x94NHxe2x80x94C(O)[CHCH2CH3]xe2x80x94, then Ar is not 2-methylphenyl and is named as 7-[8-methyl-3-(tetrahydropyran-4-ylaminocarbonylmethyl]-4-(3H)-quinazolinon-2-yl)methyl-16-[(R)-(2-methylphenylaminocarbonyl)prop-1-yl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane.
Preferably, the linker X is a group of the formula:
xe2x80x94Xaxe2x80x94Zaxe2x80x94(Yaxe2x80x94Za)mxe2x80x94Xaxe2x80x94
wherein:
m is an integer of from 0 to 20;
Xa at each separate occurrence is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NRxe2x80x94, xe2x80x94N+RRxe2x80x2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)NRxe2x80x94, xe2x80x94C(S), xe2x80x94C(S)Oxe2x80x94, xe2x80x94C(S)NRxe2x80x94 and a covalent bond where R and Rxe2x80x2 as defined below;
Za at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, substituted arylene, substituted heteroarylene, substituted heterocyclene, and a covalent bond;
each Ya at each separate occurrence is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94NRxe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94C(O)NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2 C(O)xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94C(O)NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2 C(S)NRxe2x80x2xe2x80x94, xe2x80x94C(xe2x95x90NRxe2x80x2)xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94C(xe2x95x90NRxe2x80x2)xe2x80x94, xe2x80x94OC(O)xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94P(O)(ORxe2x80x2)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94P(O)(ORxe2x80x2)xe2x80x94, xe2x80x94S(O)nCRxe2x80x2Rxe2x80x3xe2x80x94, xe2x80x94S(O)nxe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94S(O)nxe2x80x94, xe2x80x94Sxe2x80x94Sxe2x80x94, and a covalent bond; where n is 0, 1 or 2; and R, Rxe2x80x2 and Rxe2x80x3 at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic provided that at least one of Xa, Za, and Ya is not a covalent bond.
In a second aspect, this invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
In a third aspect, this invention is directed to a method for producing local anesthesia in a mammal which method comprises administering to a mammal in need of such treatment a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
In a fourth aspect, this invention is directed to a method for modulating the activity of a Na+ channel in a mammal, which method comprises administering to said mammal a Na+ channel modulating amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
In a fifth aspect, this invention is directed to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament. Preferably the medicament is used for producing local anesthesia in a mammal.
In a sixth aspect, this invention is directed to processes for preparing compounds of Formula (I).
In a seventh aspect, this invention is directed to novel intermediates useful or preparing compounds of Formula (I) or pharmaceutically acceptable salts hereof.